This invention relates to the diagnosis and treatment of tumors having peptide-specific surface receptors.
Despite the advances in diagnosis and treatment of cancer, surgery remains the most reliable and effective long-term treatment of some types of cancer. The success of surgery is limited by precise and complete preoperative or intraoperative localization of tumors, an imprecise and incomplete assessment of the disease occurs in 20% to 40% of cancer cases. While various preoperative imaging techniques are available, the sensitivity of these techniques is proportional to tumor size. For example, the lower limit of resolution in CT scanning is 0.8 cm to 1.0 cm. Superselective angiography is more successful in tumor localization, but requires highly experienced technical expertise. Tumor localization techniques which do not rely on imaging, such as percutaneous transhepatic portal venous sampling (PTPVS), have been used successfully to regionally localize small functional tumors undetected by other methods. Still, these tumor localization methods are limited. For example, PTPVS does not routinely allow the individual assessment of nodal positivity or negativity and may not detect multicentric tumors.
When preoperative tumor localization fails, the clinician must next resort to exploratory surgery combined with intraoperative tumor localization and resection. Aggressive intraoperative localization is accomplished with a combination of ultrasound, palpation, and endoscopic or laparoscopic techniques. While these techniques allow the detection of small tumors undetected by available preoperative localization techniques, small tumors outside of the organs inspected may remain undetected. Moreover, morbidity resulting from exploratory surgery increases as more tissue is disturbed.
A variety of cancers, including both endocrine and non-endocrine tumors, express somatostatin receptors. Five human somatostatin receptors have been identified and cloned. Expression of these five receptor subtypes varies with tissue types. Somatostatin receptor subtype 2 is expressed on a wide variety of tumor types. Tables 1A and 1B provide a summary of somatostatin receptor expression in both normal and tumor tissues.
TABLE 1A ______________________________________ Somatostatin Receptor Subtype Expression in Normal Human Tissue Normal Human Receptor Tissue Subtype Reference ______________________________________ Frontal SST2, SST1, Yamada et al., Proc. Natl. Acad. Cortex SST3, SST5 Sci. USA, 89:251-255, 1992; Rohrer et al., Proc. Natl. Acad. Sci. USA, 90:4196-4200, 1993 Liver SST2 (low) Yamada et al., supra Lung SST1 Rohrer et al., supra Stomach SST1 Yamada et al., supra Intestine SST1 Yamada et al., supra (jejunum) Pancreas SST1, SST3 Yamada et al., supra Colon SST1 (low) Yamada et al., supra SST2 (low) Kidney SST2 Yamada et al., supra ______________________________________
TABLE 1B ______________________________________ Somatostatin Receptor Subtype Expression in Human Tumor Tissue Human Tumor Receptor Tissue Subtype Reference ______________________________________ Lung SST2 Patel et al., Biochem. Biophys. Res. Commun., 198:605-612, 1994 Carcinoid SST2, SST1, Patel et al., supra SST3 Insulinoma SST3 Reubi et al., Cancer Res., 54:3455-3459, 1994 ACTH SST1, SST2 Reubi et al., supra Secreting CLL SST2 Patel et al., supra Neuro- SST2 Patel et al., supra blastona Breast SST2 Patel et al., supra Colon SST1 Yamada et al., Proc. Natl. Acad. Sci. USA, 89:251-255, 1992 Hepatoma SST2 Yamada et al., supra Pituitary SST2, SST3 Reubi et al., supra Prolactino ma Pituitary SST2, SST1, Patel et al., supra; Reubi Adenoma SST3 et al., supra Meningioma SST2 Patel et al., supra ______________________________________
Endogenously produced somatostatin inhibits release of several pituitary and intestinal factors that regulate cell proliferation, cell motility, and/or secretion including growth hormone, adrenocorticotropin hormone, prolactin, thyroid stimulating hormone, insulin, glucagon, motilin, gastric inhibitory peptide (GIP), vasoactive intestinal peptide (VIP), secretin, cholecystokinin, bombesin, gastrin releasing peptide (GRP), gastrin, adrenocorticotropic hormone (ACTH), thyroid releasing hormone (TRH), choleocystokinin (CCK), aldosterone, pancreatic polypeptide (PP), cytokines (e.g., interleukins, interferons), growth factors (e.g., epidermal growth factor, nerve growth factor), and vasoactive amines (e.g., serotonin). Several of these factors are implicated in regulation of normal cell proliferation, as well as in tumor cell proliferation and/or metastasis. For example, GRP stimulates proliferation of normal and malignant intestinal epithelial cells, stimulates the proliferation of normal bronchial epithelial cells, and is an autocrine growth factor in small cell lung carcinoma.
Somatostatin-14 (S-14) and somatostatin-28 (S-28) are the two principal forms of native somatostatin. S-14 is a 14-amino acid peptide having the sequence Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys (SEQ ID NO:1). The amino acid sequence of S-14 is highly conserved among vertebrate species. S-14 has a cyclic molecular structure stabilized by a disulfide bond between Cys.sub.3 and Cys.sub.14 (the cysteines at positions 3 and 14 from the N-terminus) and by hydrogen and hydrophobic bonds. Four amino acids within the ring structure of somatostatin, Phe.sub.7 -Trp.sub.8 -Lys.sub.9 -Thr.sub.10 (SEQ ID NO:2), are primarily responsible for receptor binding and biological activity, while the residues Trp.sub.8 -Lys.sub.9 are predominate in receptor binding. S-28 is a 28-amino acid peptide and contains the amino acid sequence of S-14 with an additional 14 amino acids extending from the N-terminus. The structural differences in S-14 and S-28 influence the relative degrees of inhibitory activity on the biological functions regulated by somatostatin.
A variety of somatostatin peptide analogs have been produced by elimination of amino acids that are not absolutely required for activity and/or substitution of the native L-amino acids with the corresponding D-amino acid isomers. Thus, some of these analogs are longer acting, more potent receptor agonists than native somatostatin, due in part to the resistance of D-amino acids to enzyme degradation. For example, the synthetic somatostatin analog octreotide acetate, which has the amino acid sequence D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr(ol) (SEQ ID NO:3), is 45 to 70 times more potent than native somatostatin in inhibition of growth factor release. LANREOTIDE.TM., a synthetic somatostatin octapeptide analog having the amino acid sequence D.beta.-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr(NH.sub.2) (SEQ ID NO:4), is 20 to 50 times more potent than native somatostatin.
The use of somatostatin analogs in diagnosis and therapy is limited by the relatively short half-life of these analogs in vivo. Moreover, tumor localization techniques using detectably labeled somatostatin analogs are limited by the amount of detectable label that can be associated with each analog, the strength of the signal generated per analog molecule, and the sensitivity of available label detection techniques. There is a clear need in the field for both diagnostic and therapeutic methods which allow for highly specific and sensitive identification of tumor cells, as well as less invasive cancer therapy regimens.